We have previously shown that generation of the potent reactive nitrogen species (RNS) peroxynitrite (PN) is responsible for oxidative damage by lipid peroxidation (LP) and protein modification (carbonylation and tyrosine nitration) to mitochondrial and other cellular elements during the first hrs after spinal cord injury (SCI). The PN-mediated oxidative damage leads to brain mitochondrial dysfunction and ultimately failure. As a consequence of oxidative compromise of mitochondrial function including calcium (Ca++) buffering), posttraumatic intracellular Ca++ overload is exacerbated leading to calpain-mediated cytoskeletal degradation, neurodegeneration and neurological impairment. We have further shown that treatment with the potent LP inhibitor U-83836E can partially attenuate posttraumatic brain LP damage, mitochondrial dysfunction and calpain-mediated cytoskeletal damage in a mouse TBI model. Most importantly, the window for this effect is at least 12 hrs post-injury. However, our preliminary results showing a partial attenuation of post-injury LP-related neural damage'even when the LP inhibitor is administered within the first 15 min. after injury, strongly point to the logic of an antioxidant neuroprotective strategy that combines a LP inhibitor U-83836E with the LP-derived lipid aldehyde 4-hydroxynonenal (4-HNE) scavenger phenelzine to achieve a greater degree of neuroprotection. Therefore, the overall goal of the proposed experiments is to explore the hypothesis that interrupting post-traumatic secondary oxidative damage at multiple points will produce a quantitatively greater neuroprotective effect with less variability that will have a greater chance of translational success in future SCI clinical trials. The combination approach should not only increase the maximal neuroprotective effect, but may also prolong the therapeutic window for inhibition of secondary brain injury after TBI. PUBLIC HEALTH RELEVANCE: This project will examine the potentially greater benefits that might be obtained in the rat thoracic spinal cord contusion injury model when multiple neuroprotective compounds that target oxidative secondary injury mechanisms are administered together. Specifically, we will test a dual treatment strategy involving the combination of the potent lipid peroxidation-inhibiting drug U-83836E with phenelzine, a commercially available compound that scavenges the neurotoxic lipid peroxidation-derived lipid aldehyde 4-hydroxynonenal (4-HNE). Each of the compounds will also be tested by themselves in order for comparison to the combination treatments.